A (7:04)

Our next article this month is a very important article from the New England Journal of Medicine and is titled Tirzepatide for Heart failure with Preserved Ejection fraction and Obesity. And we are privileged to have joining us to discuss this article, one of the authors, Dr. Christopher Kramer. Dr. Kramer is chief of the Cardiovascular division of the University of Virginia School of Medicine. Welcome, Chris.

C (7:34)

Thanks for having me.

A (7:35)

Chris, can you talk to us about why the article was done? A little bit of background on this.

C (7:41)

Yeah. So we certainly know that GLP1 agonists are beneficial for weight loss. We know that they benefit patients with diabetes. We know from the Stop HFpEF trial that they are. Or step HEFpEF, excuse me, that they benefit patients with HFREF in terms of they feel better HFpEF, excuse me. So HFPEF is heart failure with preserved ejection fraction. And they're really a paucity of therapies for that condition. And in the Step HFEF trial, patients on semaglutide felt better at the end of the trial compared to those treated with placebo. And it was noted that there was leads a trend to fewer heart failure events on therapy. And the Summit trial was actually designed before the STEP HFPEF results were known, but it was designed to test the combined GLP1 and GIP receptor agonist tirzepatide in patients with HFpEF. And based on the STEP HFPEF design, it was designed as an event driven trial. The idea was, do these agents reduce heart failure events in patients with obesity related HFpEF?

A (9:02)

You know, it's interesting and in that way they are. The endpoint is a lot more similar to the typical SGLT2 trials, right? That these are heart failure events.

C (9:13)

Yes. Yep, absolutely. So the composite endpoint here was cardiovascular death and heart failure events, which included heart failure hospitalizations as well as outpatient increase in diuretic regimen.

A (9:29)

And can you tell us briefly the methodology?

C (9:32)

Yeah. There were 731 patients with heart failure that were recruited into the trial. They had to have an EF of at least 50%, a BMI of at least 30 and they were randomized to receive tirzepatide starting at 2.5 milligrams subcutaneously per week and then ramped up over time to 15. And they were treated for at least 52. And it was, as I mentioned, placebo controlled. The endpoints were that combined endpoint I mentioned.

A (10:06)

Excellent. And what did the results show?

C (10:09)

Well, the results showed a benefit to the therapy with tirzepatide. The hazard ratio for the combined endpoint was 0.64. So fewer events in the tirzepatide treated group. That was primarily driven by heart failure events, mostly heart failure hospitalizations. There was no difference, absolute difference in the numbers of cardiovascular events similar in both. Excuse me, cardiovascular death similar in both groups. It was really driven by reduction in heart failure events. And then there were a number of other endpoints that were examined.

A (10:47)

And I noticed one of the endpoints was a symptom score, I guess the Kansas City KCCQCSS score that also showed that symptoms were improved. Not only did people have less events, but also felt better. Is that correct?

C (11:04)

That's correct. They felt better actually. So the KCCQ or Kansas City Cardiomyopathy Questionnaire is a well validated questionnaire used in heart failure trials and is really a measure of symptom extent. And yes, the KCCQ score increased significantly in the treated group. It increased a little bit in the placebo, but far statistically significantly more in the treated group. So patients definitely felt better on drug.

A (11:36)

And the other thing I found interesting, the average duration of follow up was 104 weeks. So this all occurred over a relatively short period. Period of time.

C (11:50)

Yeah, the randomized portion was 52 weeks. And yes, it was over a year. And we know that weight loss on these drugs continue for out to 72 weeks. So it's possible that if it extended the follow up that there would be even more benefit over time.

A (12:09)

Interesting. So what do you see as the clinical implications of this trial?

C (12:14)

Yeah, I think it's a very important study that shows that GLP1s, as we're learning, have multiple beneficial effects in patients with obesity. And when it comes to heart disease, we know that they now that they benefit patients with heart failure with preserved ejection fracture not only in improving symptoms, but also in reducing heart failure hospitalization, heart failure related events. And so another arrow in the armamentarium to try to work on improving the lives of patients with obesity related HFpEF.

A (12:49)

Yeah, and this is a big deal, I'll say because I think HFpEF is one of those things that as we begin looking for it more, we're beginning to find it. I think the New York Heart association criteria for entry in a lot of the HFPEF Trials was Class 2, which is shortness of breath or, or fatigue with usual activities, which doesn't take much if I think of the patients. I see. And years ago there was no treatment available. Now we have SGLT2s, clearly robust data. I guess the phenerinon trial not that long ago, semaglutide and now tirzepatide.

C (13:34)

Yeah, and Arnie's as well have shown some benefit and have HFpEF. So we've gone from zero to 60 very quickly over the last three or four years in HFpEF where we we've had four pillars of therapy in HEF for the last couple of years with when Once Arnie's and SGLT2s were added to the armamentarium. Now we have, you know, three or four classes of drugs in HEF PEF that are beneficial. We'll have to see, you know, relative benefit of these drugs over time.

A (14:03)

It is going to be interesting. Dr. Chris Kramer, thank you so much for joining us.

C (14:09)

Thanks again for having me.

A (14:11)

Our next article is from JAMA Internal Medicine titled effectiveness of empagliflozin versus dapagliflozin for kidney outcomes and type 2 diabetes. There are no large randomized clinical trials that have directly compared EMPA versus DAPA for their outcome on kidney outcomes. So the goal of this trial was using something called a target trial emulation design, basically a real world study to compare kidney outcomes between those people who initiated empagliflozin versus dapagliflozin in adults with type 2 diabetes. This was a Danish healthcare data set. From 2014 to 2020 there were a total of over 32,000 individuals who initiated treatment with EMPA and 17,000 with DAPA. Mean age 63. Notice the mean EGFR here was actually very good. 88 people who initiated treatment with EMPA and DAPA exhibited comparable six year risks of acute kidney injury, chronic kidney disease, both as measured by EGFR or albuminuria as well as progression of chronic kidney disease.

B (15:31)

John so another interesting study, the caveat as all of these studies, it's a Danish study, there might be something intrinsic to a homogeneous population that might not play everywhere, but I don't think that's the real takeaway point from the study. I think this is the whole thing about class effect. We love class effect and for people who manage healthcare systems, they really love to have 10 different aces when we can kind of mix and match and put you on anything. And to me I think this is really overwhelming data that you have really two strong contenders that all the confidence intervals are all the same, that you can use either medicine very confidently and get the same effect. I don't think the leap though is everything else in the SGLT2 category suddenly can. Can claim the same amount. And I think we're going to have to see some more contenders. When we looked at mace impact by the the GLP1s or the SGLT2s, it had most of the people were in the boat, but not everyone. When we think about the TZDs, right? One of the TZDs pulled from the market, another one's still perfectly good medicine that we'll use. In diabetes, all the statins probably decrease inflammation, decrease cardiovascular, but really when we look at high risk people, we really selected out the high potency statins. So I think right now I would kind of take away that you can, if you need a little mnemonic Ed, we can all certainly kind of remember that for kidney protection for that and maybe there'll be some more letters and that mnemonic in the future. Anytime that we can protect someone's kidneys. I think that's a very exciting thing. When I look at the challenge that you and I have in primary care and that our young residents will have over the next 15 years, I think one of the largest challenges we're going to have is how can we keep the people who are in CKD 3 and 4 from not moving to 5. I think that's a huge thing and this tells us we have two very well matched champions who either one would fight the fight well for us. Our next article is from Diabetes Care and it looked at tirzepatide associated with reduced abenoneuria in patients with type 2 diabetes. A pooled post hoc analysis from randomized active and placebo controlled studies that put together the surpass one through five clinical trials. So this post hoc analysis examined data from the Overall pooled surpass 1 through 5 population and subgroups defined by baseline having a urine albumin to creatinine ratio greater than 30 milligrams per gram. A mixed model for repeated measures was used to analyze on treatment data from baseline to the end of treatment visit. The adjusted mean percentage change from baseline urine album and creatin ratio for tirzepatide 5, 10 or 15 milligrams compared with all comparators was a decrease in 19.3%, a decrease in 22% and a decrease in 26.3% respectively, and they looked at weeks 40 and 42. Results were similar across pooled placebo active and insulin comparator studies. The urinary albumin creatinine ratio alone appeared more profound in subgroups who had that albumin creatinine ratio greater than or equal to 30 milligrams per gram. Mediation analysis findings suggested approximately 1/2 the reduction in aminuria associated with tirzepatide may be weight loss related. There was no difference in EGFR between tirzepatide and the pooled comparators at weeks 40 to 42.

A (19:32)

Neal John, this is a helpful analysis to confirm what we would suspect, right that tirzepatide has beneficial effects on the kidney, that it decreases albuminuria. It remains to be seen and we would love to see a study showing an effect on EGFR decreasing progression of chronic kidney disease. You know, this has become a really interesting area with a lot of choices now. So for for years we've had Rasi inhibitors, ACEs and ARBs in our armamentarium for kidney disease, then SGLT2s, very powerful agents, then the non steroidal MRA antagonists, phenirenon, all of these working through different mechanisms. And then back almost a year ago now we saw the flow study of semaglutide and its beneficial effects on kidney outcomes and actually also decreasing cardiovascular outcomes in people with chronic kidney disease and diabetes. Now we see this article with tirzepatide. The CADIGO guidelines that came out about a year ago were very helpful in helping us know when to use which agent. Neither of the GLP1 trials had come out when the CADIGO guidelines were issued. They mentioned them, but they mentioned that it was not clear yet where they fit in because the data was not released yet. It's going to be a challenge to figure out moving forward. Is this going to be the four pillars of kidney care similar to the way that we treat for instance heart failure with reduced ejection fraction? Everyone gets four drugs or is it going to be that some people get one drug or two drugs, et cetera? We will continue to figure this out. It is exciting to be a part of this march of scientific progress where there is more and more we are able to do for people. It's pretty clear now that part of the approach for at least some people with chronic kidney disease and diabetes is going to be the GLP1s and the GLP1 dual agonists. Our final article this month is from Diabetes Care and is titled Use of SGLT2 inhibitors versus DPP4 inhibitors as an add on Therapy and the Risk of Peripheral Artery Disease related surgical events I.e. amputation, stent placements or Vascular surgery. Joining us to discuss this article, we are privileged to have one of the authors, Dr. Christine Roumie, Dr. Christiane Rumi, who is a professor of medicine in the Division of General Internal Medicine and Public Health at Vanderbilt School of Medicine and Director of the vetwise LHS center of Innovation at the VA Tennessee Valley Healthcare System. Christiane, welcome to our podcast.

D (22:49)

Thank you so much for having me here.

A (22:52)

This was such an important article. Can you share with us some background about this topic, why you all chose to look at this?

D (23:02)

Well, yes, thank you. More than 30 million Americans have diabetes and it's a condition that carries a lot of risk for heart disease. And there were a number of pivotal clinical trials that demonstrated the benefits of SGLT2 to reduce major adverse cardiovascular events. But in some of those trials there was also this signal for amputations. And so we chose to further explore that in a real world effectiveness study which included a large cohort of older veterans with diabetes.

A (23:47)

This is so important because I remember when this issue first came up with the Canvas trial and there was enough information that led to a boxed warning that then was retracted because subsequent trials the what was a credence and declare didn't show that. So it is still somewhere, I'll say buried in the product information. But it's certainly not a boxed warning and I think it's been an area that most of us as clinicians have heard about and are uncertain about. So this is an important article to an important issue to look at. How did you go about examining this?

D (24:31)

So as I said, it's a real world effectiveness study which includes a very large cohort of older veterans with diabetes. They received care at the VA between 2000 and 2021. We collected all their routine care, their comorbid conditions, and we accounted for those as well as the duration of diabetes. So most patients had diabetes for in excess of 10 years and they needed to continue on their diabetes medication. And then we measured the effect of an SGLT2 added on that medication regimen or a DPP4 added on that regimen. And then we looked at specific outcomes which didn't just include amputation, but it was broader. It included surgical procedures for revascularization. So we really wanted to try to capture early onset peripheral artery disease as part of the outcomes. So we followed veterans over time we had up to five years of follow up for some veterans and really saw that the DPP4 was, is considered cardiac neutral. So it served as a nice comparator. And that compared to DPP4, addition of SGLT2s was associated with an increased cause specific hazard of peripheral artery disease surgeries compared to the DPP4. And what I mean by cause specific hazard is it looked like there was an increased association with peripheral artery disease in the presence of death as a competing risk. So the SGLT2 is a little protective against cardiovascular death. And in the face of that protection, you have longer time to sort of develop peripheral artery disease and that becomes a more prominent association.

A (26:49)

Oh, that's fascinating. So when you say there is someone is living longer so that they have a longer period of time where they can develop peripheral artery disease, is that why or do you control for that in your analysis?

D (27:06)

So we do control for age and we control for the duration of medication that you're like how long you continued on your SGLT2 or the DPP4 as comparison. So, you know, once you stop the drug, we looked for events that could happen within the first kind of 90 days after that, because as you know, peripheral artery disease has a long time course. So somebody could develop a toe ulcer and then get hospitalized. Somebody might change their SGLT2 regimen and then they might go on and develop a revascularization procedure. If all of that happened in the first kind of 90 days, we counted that as an event. We do another sensitivity analysis where we follow people out for up to a year after they stop drug. And that effect was still there, it was lessened, but it was still there. That you could really, just because of the long time course of peripheral artery disease, you could develop those risks and not have your surgical procedure or amputation for up to, you know, three months or six months after you stop the drug.

A (28:27)

Right. And so that we have a sense of both the robustness of the data and the level of effect. The number of people in this trial was large. There was over 75,000 people in each of the two groups. It's pretty amazing the VA data set allows one to really look so carefully at so many questions, this being one. So we have a large cohort of individuals. The average age here, I know is 69. What was the level of effect?

D (29:01)

Yeah, so we found about a 15% increased risk, and I use the word risk very loosely. It's an association of an increased risk of about 15 or 16% for those who use SGLT2 compared to DPP4. It's interesting because there's, I think some of the issues around the black box warnings and the guidance have been specifically for canagliflozin and most of our users were empagliflozin users within the VA dataset. So we, we did not have a lot of canagula flows and users. It's not like that was kind of entirely driving the results. But I think some of the issues around, well, what's the mechanism for this? Are really still fairly unknown and there have been a lot of hypothesized mechanisms and so it's, it's hard to kind of put out a black box warning when you don't know why this might be happening. There have been postulated, you know, there's decreased intravascular volume, there's a lack of control of diabetes. I think the bottom line is we're not sure why this happens, but that signal is there. There happened in the clinical trials. We detected it in this, you know, observational study and real world effectiveness study of meds.

A (30:47)

Now let me ask you a question. In this sort of study, are you able to, we talked about the, that you detected a hazard ratio or a relative increase in risk of 15%. Is there the ability to look at an absolute increase in risk? I know in the first place part of your paper you quoted the results of the Canvas trial and there, there was a 6.3 versus a 3.4 events per thousand person years. That was the difference. Is there a way in this sort of study to have a sense of absolute risk which becomes important when we think about how to use information clinically.

D (31:34)

So in our study we found event rates of 11 versus 10 per thousand person years. So it's about a 1 per thousand person years use. So if you use, if there are a thousand people using SGLT2 for a year, which is pretty common and is believable, there may be one additional peripheral vascular event. So either a revascularization surgery or an amputation.

A (32:06)

That's helpful. So now putting this all together, what do you see as the clinical implications of this study?

D (32:13)

Yeah, I think for us, we like myself and our co authors, believe that the SGLT2s are a really important drug class. They have really transformed management of diabetes. However, we need to be really thoughtful and risk stratify the people that are using this and not just kind of blanket them all with SGLT2. And so our call is for a little more risk stratification before we just start Everybody on an SGLT2, particularly older people who might have had diabetes for in excess of 10 years and are at very high risk of peripheral vascular disease. If we can do some screening. Abis as a clinician, I think this is a strategy. I have zero evidence for this, but I think as a good clinician, you want to be sure that you're putting people on the right drug at the right time. And so if we can gain a little more evidence for, you know, is this safe to use in this patient, it may be worthwhile to add that sort of risk stratification into our clinical decision making.

A (33:39)

Those are helpful ideas. I mean, there's no question that for all medicines, when we decide what to do for patients, we're always weighing the. The benefit, which here with SGLT2s, as you alluded to, for kidney for heart failure treatment and prevention are large. But we're always weighing the benefit and the risk. And the more we know about the risk side as well, the better we're able to proceed. Dr. Christine Roume, thank you so much for joining us, sharing your data, your expertise and wisdom.

D (34:16)

Thank you so much for having me. I look forward to seeing you at the scientific sessions.

A (34:23)

For more information and links to the articles that we discussed in this issue, just go to diabetesjournal.org until next month.

B (34:34)

Keep listening and keep learning.